The human immunodeficiency virus type 1 (HIV-1) frequently infected hemophiliacs who received non-heat-treated clotting factor concentrates prior to 1985. In addition, these individuals were universally infected by hepatitis C virus (HCV) with >80% remaining chronically infected. Thus, hemophiliacs represent an important population for studies of the natural history of these chronic viral infections. Moreover, the high rate of co-infection makes it an ideal group for assessing the interaction between the viruses and the relationship between viral-specific immune responses and clinical progression. Co-infection by these chronic viral pathogens is becoming increasingly common, particularly among intravenous drug users, who account for approximately 25% of the epidemic in the United States. We have investigated issues related to HIV-1 and HCV immunopathogenesis by studying children and adolescents enrolled in the Hemophilia Growth and Development Study (HGDS). The HGDS enrolled 333 hemophiliacs of whom 207 are HIV-1 co-infected, between 1989 and 1990 and followed them for 7-8 years. A total of 332 hemophiliacs had 1-8 repeated annual HCV RNA measurements between baseline and 7 years of follow-up. CD4+ cells and plasma HCV RNA were measured annually in all subjects, and plasma HIV RNA was measured annually in the HIV-infected subjects. We have previously reported that high HCV viral load was associated with increased morbidity and mortality in HIV-1 co-infected hemophiliacs and that HIV-1 infection was associated with increased risk of persistent HCV infection. We are now investigating the role of viral-specific immunologic responses in controlling HIV-1 and HCV replication and how these responses are regulated by the immune system. Genetic polymorphisms that affect T cell differentiation may influence Th1/Th2 balance and the effectiveness of the immune system in mounting a cytotoxic response to specific HIV-1 and HCV epitopes. We have identified single nucleotide polymorphisms in regulatory or noncoding regions of cytokines known to have a role in determining Th1/Th2 states. These will be analyzed for correlations with the strength and breath of cytotoxic T lymphocytes (CTL) immune responses to HCV and/or HIV viral peptides. We have completed HCV genotyping on the entire HGDS cohort and are now investigating the role of HCV genotype on HIV-1 clinical progression to AIDS and on HIV-1 RNA levels. We have complete genotyping for single nucleotide polymorphisms (SNPs) in more than 100 genes, including APOBEC3G and TRIM5, that are involved in immune regulation, viral entry, and the successful completion of the viral life cycle. Host genetic variation in HIV-1 chemokine co-receptors and their ligands have been shown to modify rates of HIV-1 progression by altering surface expression and availability of co-receptors for HIV-1 binding. However, their influence on HIV-1 viral load is less well defined. We have tested the effects of more than 100 SNPs on HCV clearance and have identified several immune response modifiers that influence clearance. The identification of genetic factors that influence HIV or HCV pathogenesis by restricting viral replication may provide targets for potential therapeutic intervention or provide clues to factors involved in successful immune regulation by CTLs.